We propose a continuation of the North Carolina Ovarian Cancer study (NCOCS), a molecular epidemiologic study of primary epithelial ovarian cancer. This is a population-based, case-control study in a 48 county region of North Carolina. We will have enrolled approximately 500 invasive epithelial ovarian cancer cases by the start of the proposed study, and plan to enroll 300 additional cases. The central goal of the NCOCS is to define subsets of epithelial ovarian cancer on the basis of the molecular signatures associated with specific disease causing exposures. The proposed renewal application will focus on the role of genes in DNA damage response pathways in the development of ovarian cancer. We hypothesize that spontaneous errors of DNA synthesis during cell proliferation is induced by ovulation leading to tumor development and individual variation in the efficiency of repairing damaged DNA due to variants in genes in DNA damage response pathways may be associated with ovarian cancer risk. In addition we hypothesize somatic p53 mutations, the most common molecular alteration in ovarian cancers, may interact with variants in DNA damage and repair genes resulting in failed DNA repair. The specific aims are: 1) To continue accrual of ovarian cancer cases and controls to achieve a sample of 800 invasive ovarian cancer cases and 800 controls; 2) To examine the relationship between ovarian cancer risk and polymorphisms in DNA damage and repair genes including XRCC1, XPD, BARD1, BACH1, GADD45, and BASC. We will also examine polymorphisms in genes involved in the p53 DNA damage checkpoint including p21, MDM2, AFR, and PIG3 genes; and 3) To develop a high throughput approach to identification of single nucleotide polymorphisms (SNPs) that affect ovarian cancer susceptibility. The joint consideration of epidemiologic risk factors and molecular characteristics should enhance our understanding of the etiology of ovarian cancer. Elucidation of the role of reproductive and environmental risk factors and genetic susceptibility could facilitate identification of high-risk women who would be ideal candidates for preventive interventions.